The overall objective of this project is to investigate the role of Atrial Natriuretic Peptide (ANP) in the lung. ANP is an endogenous cardiac hormone which is released by distension of the heart and is known to relax the smooth muscles of the blood vessels in addition to its natriuretic and diuretic properties. Thus, ANP appears to be an important regulator of blood pressure. However, the presence of a large amount of ANP has been demonstrated in the lung. An increase in plasma ANP levels has also been observed in several pulmonary pathological conditions. Yet, little is known about the function of ANP in the lung, particularly regarding its ability to relax the smooth muscles of the airways. The hypotheses to be tested are: 1) ANP works on the airways without the intervention or interaction of systemic mediators or the influence of the centrally mediated reflexes, 2) Airway epithelium, particularly by its action of the neutral endopeptidases, modifies the effect of ANP on the lung, 3) ANP acts directly on the smooth muscle cells of the airways and not through the release of other intermediary compounds, 4) ANP acts on the airways through cGMP as a second messenger, and 5) ANP acts primarily on the central airways rather than on the peripheral airways. The specific aims are l) To study the action and potency of ANP in isolated-perfused lungs where the airway responses have been altered by bronchoactive agents. 2) To study the role of airway epithelium, particularly its neutral endopeptidases, on the action of ANP on lung mechanics. 3) To study the role of endothelial derived relaxing factor (EDRF) and cyclooxygenase inhibitors on the action of ANP on lung mechanics. 4) To determine if ANP acts on the airways through cGMP as the second messenger. 5) To determine the site of action of ANP within the airways. The proposed research is significant in that by establishing how ANP regulates bronchodilation it may lead to new therapies particularly for conditions of combined atrial stretch and airway dysfunction such as cardiac asthma, congestive heart failure and cor pulmonale associated with chronic obstructive pulmonary diseases.